Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cancer cell (Impact Factor: 23.52). 03/2009; 15(2):135-47. DOI: 10.1016/j.ccr.2008.12.016
Source: PubMed


The growth of many cancers depends on self-renewing cells called cancer stem cells or tumor-propagating cells (TPCs). In human brain tumors, cells expressing the stem cell marker CD133 have been implicated as TPCs. Here we show that tumors from a model of medulloblastoma, the Patched mutant mouse, are propagated not by CD133(+) cells but by cells expressing the progenitor markers Math1 and CD15/SSEA-1. These cells have a distinct expression profile that suggests increased proliferative capacity and decreased tendency to undergo apoptosis and differentiation. CD15 is also found in a subset of human medulloblastomas, and tumors expressing genes similar to those found in murine CD15(+) cells have a poorer prognosis. Thus, CD15 may represent an important marker for TPCs in medulloblastoma.

Download full-text


Available from: Shirley Markant
  • Source
    • "Approximately 17.6% (3 out of 17 PtenFloxp/+) of mice expressing one allele of Ptch1 developed symptoms of medulloblastoma by 1 year of age. Most of these mice died 5 months after birth[22],[23]. However, PtenFloxp/+ PtenFloxp/+ GFAP-Cre mice died of medulloblastoma from 2 months after birth. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Medulloblastoma is the most common malignant pediatric brain tumor. Some are thought to originate from cerebellar granule neuron progenitors (CGNPs) that fail to undergo normal cell cycle exit and differentiation. The contribution of microRNAs to the initiation and progression of medulloblastoma remains poorly understood. Increased expression of the miR-183∼96∼182 cluster of microRNAs has been noted in several aggressive subgroups. We identified that expression of miR-183∼96∼182 was higher in medulloblastomas with Pten gene loss in the background of the activated sonic hedgehog (Shh) signaling pathway. Ectopic miR-183∼96∼182 expression in CGNPs synergized with exogenous Shh to increase proliferation and its role depended on hedgehog signaling activation. Our findings suggest a new microRNA cluster, the miR-183∼96∼182, functionally collaborates with the Shh signaling pathway in the development of medulloblastomas in mice.
    Preview · Article · Nov 2013
  • Source
    • "Increasing evidence indicates that Hh signaling is critical for cancer stem cell maintenance and function.138,175,176 For example, leukemia stem cell maintenance and expansion are dependent on Hh signaling.138,175 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since its first description in Drosophila by Drs Nusslein-Volhard and Wieschaus in 1980, hedgehog (Hh) signaling has been implicated in regulation of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of Gorlin syndrome in 1996 by two independent teams. Later, it was shown that Hh signaling may be involved in many types of cancer, including skin, leukemia, lung, brain, and gastrointestinal cancers. In early 2012, the US Food and Drug Administration approved the clinical use of Hh inhibitor Erivedge/vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. With further investigation, it is possible to see more clinical applications of Hh signaling inhibitors. In this review, we will summarize major advances in the last 3 years in our understanding of Hh signaling activation in human cancer, and recent developments in preclinical and clinical studies using Hh signaling inhibitors.
    Full-text · Article · Oct 2013 · OncoTargets and Therapy
  • Source
    • "It has been reported recently, that CD133 is only expressed in a subset of glioblastomas [43], while observation of abundant nestin expression is in complete agreement with several previous reports that came to the same conclusion [35]–[37]. Furthermore, specific CD15 immunoreactivity on BTSCs has been described by several groups [38], [39], [44], [45]. We did observe a small number of apparent CD15+ cells that were judged to be astrocytic glioma cells, based on size. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aquaporin-9 (AQP9) is a membrane protein channel that is permeable to a range of small solutes, including glycerol, urea and nucleobases. Expression of AQP9 in normal brain is limited, while widespread AQP9 expression has previously been reported in human glioblastoma. However, the specific cellular expression of AQP9 in glioblastoma remains unclear. In this study, we have examined microarrays to corroborate AQP9 mRNA expression in glioma. These analyses suggested that AQP9 mRNA expression in glioblastoma is primarily explained by tumor infiltration with AQP9 expressing leukocytes. Immunolabeling confirmed that within tumor regions, AQP9 was expressed in CD15(+) and Calgranulin B(+) leukocytes, but also in larger cells that morphologically resembled glioma cells. Specificity of immunoreagents was tested in recombinant cell lines, leukocyte preparations, and sections of normal human brain and liver tissue. Apparent AQP9(+) glioma cells were frequently observed in proximity to blood vessels, where brain tumor stem cells have been observed previously. A fraction of these larger AQP9 expressing cells co-expressed the differentiated astrocyte marker GFAP. AQP9 expressing glioma cells were negative for the brain tumor stem cell marker CD15, but were observed in proximity to CD15(+) glioma cells. AQP9 expression may therefore require signals of the perivascular tumor environment or alternatively it may be restricted to a population of glioma stem cell early progenitor cells.
    Full-text · Article · Sep 2013 · PLoS ONE
Show more